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WO2013017977A1 - Compositions et méthodes pour le traitement du cancer - Google Patents

Compositions et méthodes pour le traitement du cancer Download PDF

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Publication number
WO2013017977A1
WO2013017977A1 PCT/IB2012/053650 IB2012053650W WO2013017977A1 WO 2013017977 A1 WO2013017977 A1 WO 2013017977A1 IB 2012053650 W IB2012053650 W IB 2012053650W WO 2013017977 A1 WO2013017977 A1 WO 2013017977A1
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Prior art keywords
cancer
administration
compositions
alkyl
release
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PCT/IB2012/053650
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English (en)
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Mahesh Kandula
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Mahesh Kandula
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Publication of WO2013017977A1 publication Critical patent/WO2013017977A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • This disclosure generally relates to compounds and compositions for the treatment of cancer and its related metastasis. More partsculariy, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, enantiomers, stereoisomers, crystals, esters, salts, hydrates, prodmgs, or mixtures thereof.
  • Cancer is responsible for one in eight deaths worldwide. It encompasses more than 100 distinct diseases with diverse risk factors and epidemiology which originate from most of the cell types and organs of the human body and which are characterized by relatively unrestrained proliferation of cells that can invade beyond normal tissue boundaries and metastasize to distant organs.
  • the present invention provides compounds, compositions containing these compounds and methods for usi g the same to treat, prevent and/or ameliorate cancer and its related metastasis.
  • compositions comprising of formula 1 or pharmaceutical acceptable salts thereof.
  • invention also provides pharmaceutical compositions comprising one or more compounds of formula I or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of cancer and its related metastasis.
  • the present invention relates to the compounds and compositions of formula I, or pharmaceutically acceptable salts thereof,
  • R 1 represents hydrogen, hydroxy 1, methyl, amine, chloride (CI ), Aldehyde- (-CHO), Acetyl (-OCH3) cycohexyl methyl ether, butoxy, propoxy, thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acyi, acyialkyi, alkenyl, aikylthioa!kyl, atkynyi, alkoxyar l, alkoxyalkyl, aryl, aralkyi, aryioxyaikyl, arylthi alkyi, cycloaikyl, ether, ester, heteroaryl, heterocyclyl, lower alkyl, su!fone, sulfoxide, or hydroxyalk l
  • R 2 represents hydrogen, hydroxy 1, methyl, amine, chloride (CI ), Aldehyde- (-CHO), Acetyl (-OCH3) c
  • each i is independently 0,1,2,3.4,5.6,7 or 8; 0010] Also described are pharmaceutical formulations comprising at least one compound of the invention.
  • iOOl lJ Also described herein are methods of simultaneously regulating neuromuscular disorders and neurodegenerative diseases in a. patient in need thereof, by administering to the patient an effective amount of a compound of the invention.
  • the invention a! so includes pharmaceutical compositions that comprise an effective compound of the invention and a pharmaceutically acceptable carrier.
  • the compositions are useful for treating or preventing cancer and metastasis.
  • the compound of invention which provided as a pharmaceutically acceptable prodrug, a hydrate, a salt, such as a pharmaceutically acceptable salt, enantiomer, stereoisomer, or mixtures thereof.
  • Described herein are compounds of Formula !:
  • 1 represents hydrogen, hydroxy I, methyl, amine, chloride (CI), Aldehyde (-CHO), Acetyl (-QC3 ⁇ 4) cycohexyl methyl ether, butoxy, propoxy, thiol, alky!, alkyl thiol, acetyl thiol, disulfide, acyl, acyialkyl, alkenyl, alkylthioalkyl, alkynyi, alkoxyaryl, alkoxyalkyl, aryl, aralk i, aryloxyaikyS, ai lthioalkyi, cycloaSkyi, ether, ester, heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, or hydroxy alkyl;
  • R 2 represents
  • kits comprising any of the pharmaceutical compositions disclosed herein.
  • the kit may comprise instructions for use in the treatment of cancer and its related metastasis.
  • the application also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically accepiable carrier and any of the compositions herein.
  • the pharmaceutical composition is -formulated for systemic administration, oral administration, sustained release, parenteral administration, injection, subdermal administration, or transdermal administration.
  • kits comprising the pharmaceutical compositions described herein.
  • the kits may further comprise instructions for use in the treatment of cancer and its related metastasis.
  • compositions described herein have several uses.
  • the present application provides, for example, methods of treating a patient suffering from cancer and its related metastasis.
  • alky! refers to the radical of saturated aliphatic groups, including straight-chain alky! groups, branched-chain alkyi groups, cycloalkyl (aiicyciic) groups, alkyl-substiiuted cycloalkyl groups, and cycloalkyl-substituted alky! groups.
  • a straight chain or branched chain alkyi has 30 or fewer carbon atoms in its backbone (e.g., O-C30 for straight chains., C3-C30 for branched chains), and more preferably 20 or fewer.
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • alkyi refers to a saturated linear or branched-chain monovalent hydrocarbon radical of one to twelve carbon atoms.
  • alkyi groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), I - propyl (n-Pr, n- propyl, -CH2CH2CH3), 2-propyl (i-Pr, i -propyl, -CH(CH3)2), .1 -butyl in-Bu, n-butyl, - CH2CH2CB2CH3), 2-methy!-i -propyl (i-Bu, i-butyi -CB2CH(CB3)2), 2-butyl (s ⁇ Bu, s-butyl, - CH(CH3)CH2 H3), 2-methyi-2-propyl (t-Bu, t-butyl, -
  • alkynyS refers to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms with at least one site of unsaturation, i.e., a carbon- carbon, sp triple bond. Examples include, but are not limited to, ethynyl (-OCH), propynyl ⁇ propargyl, - CH20 H), and the like.
  • alky (or “lower alkyl) as used throughout the specification., examples, and claims is intended to include both “unsubstituted alky Is” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • Such substituents can include, for example, a halogen, a hydroxy I, a carbon l (such as a carboxyl, a alkoxycarbonyl, a formy!, or an acyl), a Ihiocarbonyl (such as a thioester, a thioaeetate, or a thioformate), an alkoxyl.
  • a halogen such as a hydroxy I
  • a carbon l such as a carboxyl, a alkoxycarbonyl, a formy!, or an acyl
  • a Ihiocarbonyl such as a thioester, a thioaeetate, or a thioformate
  • phosphoryl a phosphate, a phosphonate, a phospbsnate, an amino, an amido, an ami dine, an imine, a cyatio, a nitro, an assido, a suKhydryl, an alkylthio, a sulfate, a sulfonate, a sulfarnoyl, a sulfonamido, a stiifoii l, a heterocyclyl, an aralkyl, or an aromatic or heteroaromaiic moiety. It will be understood by those skilled in the art that the moieties substituied on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl ⁇ including phosphonate and phosphmate), sulfonyl (including sulfate, sulfonamide, sulfarnoyl and sulfonate), and silyl groups, as well as ethers, aikylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Exemplar ⁇ -" substituted alkyls are described below.
  • Cycloalky!s can be further substituted with alkyls, alkenyls, alkoxys, aikylthios, aminoaik ls, carhonyl-substituted alkyls, -CF.?, -CN, and the like.
  • acyr is art-recognized and refers to a group represented by the general formula hy drocarbyl C(OK preferably alkyl C(O)-.
  • Aryl means a monocyclic or po!ycyclic ring assembly wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring assembly. If one or more ring atoms is not carbon (e.g., N, S), the aryl is a heteroaryl. Cx aryl and Cx-Y aryl are typically used where X and Y indicate the number of carbon atoms in the ri ng.
  • acylaraiao is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbyl C(0) H-.
  • acylalkyl is art-recognized and refers to an alkyl group substituted with a acyl group and may be represented, for example, by the formula hydrocarbyl C(0)alkyl.
  • acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbyl C(0)0-, preferably alkylC(0)0-.
  • alkoxy refers to an alky! group, preferably a lower alkyl group, having an oxygen attached thereto.
  • Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • alkoxyalkyl refers to an alkyl group substituted with, an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyh aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkyl thio refers to a thiol group substituted with an alkyl group and may be represented by the general formula aikylS-.
  • alkyny refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted aSkynyls" and “substituted aikynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds.
  • substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyc!yl, or lieteroaryl groups is contemplated.
  • ether refers to a hydroearby! group linked through an oxygen to another hy drocarbyi group. Accordingly, an ether substituent of a hydrocarbyi group may be hydrocarbyl-Q ⁇ Ethers may be either symmetrica! or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocyele. Ethers include "alkoxyaJkyP groups, which may be represented by the general formula alkyl-O-aSky!,
  • heteroalkyl and “heteroaralkyP, as used herein, refers to an alkyl group substituted with a hetaryl group.
  • heteroalkyl refers to a saturated or unsaturated chain of carbon atoms and at least one heteroaiora, wherein no two heteroatoms are adjacent.
  • treateroaryl and “hetaryl” include substituted or unsuhstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatoni, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryP and heteroary also include po!ycyclic ring systems having two or more cyclic rings in which, two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromaiic.
  • the other cyclic rings can be cycloalkyls, cycloalkeny!s, cycloalkynyls. ary!s, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazoie, pyridine, pyrazine, pyridazine, and pyrirciidine, and the like.
  • the term "heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclyP refers to substituted or uiisubstituted non-aromatic ring structures, preferably 3- to 1 O-mernbered rings, more preferably 3- to 7-memhered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferabiy one or two heteroatoms.
  • heterocyclyP and heterocyclic also include poSycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycioalkyls, cycloa!fcenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroeyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morphoHne, lactones, lactams, and the like.
  • 'iwdroxyalkyr refers to an alky I group substituted with a hydroxy group.
  • lower when used in conjunction with a chemical moiety, such as, acyl, acyioxy, alky I, alken l, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer.
  • a "lower alky refers to an alkyl group thai contains ten or fewer carbon atoms, preferably six or fewer.
  • Lower a!kyls include methyl and ethyl.
  • acyl, acyioxy, alkyl, aikenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyioxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether the appear alone or in combination with other substituents, such as in the recitations hydroxyalkyi and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
  • substituted refers to moieties having substituents replacing hydrogen on one or more carbons of the backbone, it will he understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein. the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and imbranched, carbocycHc and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxy!., a carbonyl (such as a carboxyl, an alkoxyearbonyi, a formyh or an acyl), a tbiocarbony!
  • references to chemical moieties herein are understood to include substituted variants.
  • reference to an "aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
  • Substituted or unsubstituted means that a given moiety may consist of only hydrogen substituents through available valencies (unsubstituted) or may further comprise one or more non-hydrogen substituents through available valencies (substituted) that are not otherwise specified by the name of the given moiety.
  • isopropyl is an example of an ethylene moiety that is substituted by -CH3.
  • a. non- hydrogen substituent may be an substituent that may be bound to an atom of the given moiety that is specified to be substituted.
  • substituents include, but are not limited to, aldehyde, aiicyclic, aliphatic, (Ci-io) alkyl, alkyl ene, alkylidene, amide, amino, aminoalkyl, aromatic, aryS, bicycloalkyl, bieycioaryl, carbamoyl, carbocyclyl, carboxyl, carbonyl group, cycioa!kyl, cycloalkylene, ester, halo, heterobicycioalkyl , beterocycloalkytene, heieroaiyl, heterobicycloaryi, heterocyeloalkyl.
  • substituents include, but are not limited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (Ci Jo) alkoxy, (C4-12) aryloxy, hetero (Ci- io)arySoxy, carbonyl oxycarbonyl aminocarbonyl, amino, (Ci- 10) aikylamino, sulfonamide, imino, sulfonyl, sulfinyl (Ci- 0) alkyl, halo (Ci-10) alkyl, hydroxy (Ci-10) alkyl, carbonyl (Ci- 10) alkyl, thiocarbonyl (Ci JO) alkyl,
  • examples of the further subsiituent include, but are not limited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (Ci- 10) alkoxy, (C4-12) aryloxy, hetero (Ci-10) aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (Ci-10) aikylamino, sulfonamido, imino, sulfonyl, sulfinyl, (Ci-10) alkyl, halo (Ci- 10) alkyl, hydroxy (Ci-10) alkyl, carbonyl (Ci-10) alkyl, thiocarbonyl (Ci-10) alkyl, sulfonyl (Ci- 10) alkyl, sulfinyl (Ci- 10) alkyl, (Ci-10) azaalkyl, imino (Cijo) al
  • the compounds of the present invention can be present in the form of pharmaceuticall acceptable salts.
  • the compounds of the present invention can also be present in the form of pharmaceutically acceptable esters (i.e., the methyl and ethyl esters of the acids of formula 1 to be used as prodrugs).
  • the compounds of the present invention can also be solvated, i.e. hydrated. The solvation can be affected in the course of the manufacturing process or can take place i.e. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I (hydration).
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing rules of Calm, Ingo!d and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+ ⁇ or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a ixture thereof.
  • a mixture containing equal proportions of the enantiomers is cal led a "racemic mixture"
  • polymorph as used herein is art-recognized and refers to one crystal structure of a gi ven compound
  • jOOSlj “Residue” is an art-recognized term that refers to a portion of a molecule.
  • a residue of thioctic acid may be: dihydrolipoic acid, bisnoriipoic acid, tetranorlipoic acid, 6,8-bismethylmercapto-oetanoie acid, 4,6-bi smethy I mercapto- hexaiioic acid, 2,4-bismethylmeracapto-butanoi c acid, 4,6-bismethyimercapto-hexanoic acid.
  • parenteral administration and “administered parenteraliy” as used herein refer to modes of administration other than enteral and topical administration, such as injections, and include without limitation intravenous, intramuscular, intrapleural, intravascular, tntrapericardtai, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, inirademml, intraperitoneal , transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
  • a "patient,” “subject,” or “host” to be treated by the subject method may mean either a human or non-human animal, such as primates, mammals, and vertebrates.
  • compositions, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio
  • pharmaceutically acceptable carrier includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, solvent or encapsulating material involved in carrying or transporting any subject composition, from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically acceptable carrier is non-pyrogenic.
  • materials which may serve as pharmaceutically acceptable carriers include: (1 ) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxym eth l cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) po!yols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15
  • prodrug is intended to encompass compounds that, under physiological conditions, are converted into the therapeutically active agents of the present invention.
  • a common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule, in other embodiments, the prodrug is converted by an enzymatic activity of the host animal.
  • prophylactic or therapeutic treatment is art-recognized and includes administration to the host of one or more of the subject compositions, if it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i .e.. it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existina unwanted condition or side effects thereof),
  • predicting refers to assessing the probability according to which a cancer or its related metastasis related diseases patient will suiter from abnormalities or complication and/or terminal renal failure and/or death (i.e. mortality) within a defined time window (predictive window) in the future.
  • the mortality may he caused by the central nervous system or complication.
  • the predictive window is an interval in which the subject will develop one or more of the said complications according to the predicted probability.
  • the predictive window may be the entire remaining lifespan of the subject upon analysis by the method of the present invention.
  • the predictive window is an interval of one month, six months or one, two, three, four, five or ten years after appearance of the cardiovascular complication (more preferably and precisely, after the sample to be analyzed by the method of the present invention has been obtained).
  • an assessment is usually not intended to be correct for .100% of the subjects to be analyzed.
  • the term requires that the assessment will be valid for a statistically significant portion of the subjects to be analyzed. Whether a portion is staiisticaily significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, e.g., determination of confidence intervals, p-value determination.
  • Preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99 %.
  • the p-values are, preferably, 0.1, 0.05, 0.01, 0.005, or 0.0001.
  • the probability envisaged b the present invention allows that the prediction will be correct for at. least 60%, at least 70%, at least. 80%, or at. least 90% of the subjects of a given cohort.
  • treating is art -recognized and includes preventing a disease, disorder or condition from occurring in an animal which ma be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of t e disease, disorder and/or condition.
  • Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as treating the cancer or its metastasis of a subject by administration of an agent even though such agent does not treat the cause of the condition.
  • treating includes curative, preventative (e.g., prophylactic), adjunct and palliative treatment.
  • Cancer and its related metastasis includes Anal Cancer, Bladder Cancer, Brain Tumors, Breast. Cancer, Cervical Cancer, Colon/ Colorectal Cancer, Endometrial Cancer, Esophageal Cancer, Gallbladder Cancer, Head and Neck Cancer, Kidney Cancer, Leukemia, Liver Cancer, Lung Cancer, Lymphoma, Mesothelioma, Cervical cancer, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical conditio in a subject relative to a subject which does no receive the composition.
  • terapéuticaally effective amount is an art-recognized term.
  • the term refers t an amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment
  • the term refers to thai amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time.
  • the effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition.
  • One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation.
  • the pharmaceutical compositions described herein are formulated in a manner such that said compositions will be delivered to a patient in a therapeutically effective amount, as part of a prophylactic or therapeutic treatment
  • the desired amount of the composition to be administered to a patient will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions.
  • dosage values . may also vary with the severity of the condition to be alleviated, it is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art.
  • the optimal concentration and/or quantities or amounts of any particular salt or composition may be adjusted to accommodate variations in the treatment parameters.
  • treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition.
  • the dosage of the subject compositions provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials.
  • the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.
  • solvate refers to a compound formed by solvation (e.g., a compound formed by the combination of solvent molecules with .molecules or ions of the solute).
  • sustained release is art-recognized.
  • a subject composition which releases a substance over time may exhibit sustained release characteristics, in contrast to a bolus type administration in which the entire amount of the substance is made biologically available at one time.
  • one or more of the pharmaceutically acceptable excipients may undergo gradual or delayed degradation (e.g., through hydrolysis) with concomitant release of any material incorporated therein, e.g., an therapeutic and/or biologically active salt and/or composition, for a sustained or extended period (as compared to the release from a bolus).
  • This release may result in prolonged delivery of therapeutically effective amounts of any of the therapeutic agents disclosed herein.
  • systemic administration means the administration of a subject composition, therapeutic or other material at a site remote from the disease being treated.
  • Administration of an agent for the disease being treated may be termed “local” or “topical” or “regional” administration, other than directly into the central nervous system, e.g., by subcutaneous administration, such that it enters the patient's system and, thus, is subject to metabolism and other like processes.
  • the phrase "therapeutically effective amount" is an art-recognized term.
  • the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicabSe to any medical treatment, in certain embodiments, the term refers to that amount, necessary or sufficient, to eliminate or reduce medical symptoms for a period of time.
  • the effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or conditio One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation.
  • the present disclosure also contemplates prodrugs of the compositions disclosed herein, as well as pharmaceutically acceptable salts of said prodmgs.
  • This application also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the composition of a compound of Formula I may be formulated for systemic or topical or oral administration.
  • the pharmaceutical composition may be also formulated for oral administration., oral solution, injection, subdermal administration, or transdermal administration.
  • the pharmaceutical composition may further comprise at least one of a pharmaceutically acceptable stabilizer, diluent, surfactant, filler., binder, and lubricant.
  • the pharmaceutical compositions described herein will incorporate the disclosed compounds and compositions (Formula I) to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a compound of formula I or composition as part of a prophylactic or therapeutic treatment.
  • the desired concentration of formula ⁇ or its pharmaceutical acceptable salts will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art.
  • any parti ul r compound of formula 1 may be adjusted to accommodate variations in the treatment parameters.
  • treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult, or child, and the nature of the disease or condition.
  • concentration and/or amount of any compound of formula I may be readily identified by routine screening in animals, e.g., rats, by screening a range of concentration and/or amounts of the material in question using appropriate assays.
  • Known methods are also available to assay local tissue concentrations, diffusion rates of the salts or compositions, and local blood flow before and after administration of therapeutic formulations disclosed herein.
  • One such method is microdialysis, as reviewed by T. E. Robinson et ai ., 1991 , microdialysis in the neurosciences. Techniques, volume 7, Chapter I , The methods reviewed by Robinson may be applied, in brief as follows. A microdialysis loop is placed in situ in a test animal. Dialysis fluid is pumped through the loop.
  • the dosage of the subject compounds of formula I provided herein may be determined by reference to the plasma concentrations of th therapeutic composition or other encapsulated materials.
  • the maximum piasma. concentration (Crnax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.
  • an effective dosage for the compounds of Formula I is in the range of about 0.0! mg kg day to about 100 mg kg day in single or divided doses, for instance 0.01 mg/kg/day to about 50 mg/kg/day in single or divided doses.
  • the compounds of Formulas I may be administered at a dose of, for example, less than 0,2 mg kg day, 0.5 mg kg day, 1.0 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg kg day, 30 mg kg/day, or 40 mg kg day.
  • Compounds of Formula 1 may also be administered to a human patient at a dose of, for example, between 0.1 nig and 1000 mg, between 5 mg and 80 mg, or less than 1.0, 9.0, 12,0, 20.0, 50.0, 75,0, 100, 300, 400, 500, 800, 1000 mg per day.
  • the compositions herein are administered at an amount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound of formula I required for the same therapeutic benefit,
  • the amount and timing of com ositions administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the mariner of administration and on the judgment of the prescribing physician.
  • the dosages given above are a guideline and the physician may titrate doses of the drug to achieve the treatment that the physician considers appropriate for the patient.
  • the physician must balance a variety of factors such as age of the patient, presence of preexisting disease, as well as presence of other diseases.
  • compositions provided by this application may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, topically, parenteral! ⁇ ', e.g., intravenously, subcutaneously or intramedullary. Further, the compositions may be administered infranasaily, as a rectal suppository, or using a "flash" formulation, i .e., allowing the medication to dissolve in the mouth without the need to use water. Furthermore, the compositions may be admi istered to a subject in need of treatment by controlled release dosage forms, site specific drug delivery, transdermal drug delivery, patch (active/passive) mediated drug delivery, by stereotactic injection, or in nanoparticles.
  • compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses.
  • suitable pharmaceutical carriers, vehicles and diluents inciude inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • the pharmaceutical compositions formed by combining the compositions and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like.
  • These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • tablets containing various excipients such as L-argin ne, sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrates such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium iauryl sulfate and talc are often useful for tabletting purposes.
  • Solid compositions of a similar type may also be employed as fillers i n soft and hard filled gelatin capsules. Appropriate materials for this include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, etibanol, propylene glycol, glycerin and combinations thereof.
  • the compounds of formula 1 may also comprise entericai!y coated comprising of various excipients, as is well known in the pharmaceutical art..
  • solutions of the compositions may be prepared in (for example) sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • the formulations for instance tablets, may contain e.g. 10 to 100, 50 to 250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700, 800 mg of the compounds of formula 1 disclosed herein, for instance, compounds of formula I or pharmaceutical acceptable salts of a compounds of Formula I.
  • a composition as described herein may be administered orally, or parenieralSy (e.g., intravenous, intramuscular, subcutaneous or intramedullary).
  • Topical administration may aiso be indicated, for example, where the patient is suffering from gastrointestinal disorder that prevent orai administration, or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician. Localized administration may also be indicated, for example, when a high dose is desired at the target tissue or organ.
  • the active composition may take the form of tablets or lozenges formulated in a conventional manner.
  • dosage administered will be dependent upon the identity of the neoplastic disease; the type of host involved, including its age, health and weight; the kind of concurrent treatment, if any, the frequency of treatment, and therapeutic ratio.
  • dosage levels of the administered active ingredients are; intravenous, 0. 1 to about 200 mg kg; intramuscul r, 1 to about 500 rag/kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 to about 1000 mg kg; and aerosol, 5 to about 1000 mg/kg of host body weight.
  • an active ingredient can be present in the compositions of the present invention for localized use about the cutis, intranasaliy, pharyngolaryngeally, bronchially, intravaginally, reetaliy, or ocularly in a concentration of from about 0.01 to about 50% w/w of the composition; preferably about i to about 20% w/w of the composition; and for parenteral use in a concentration of from about 0,05 to about 50% w/v of the composition and preferably from about 5 to about 20% w/v.
  • compositions of the present, invention are preferably presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • unit dosage forms such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • unit dosage forms such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • sterile parenteral solutions or suspensions sterile non-parent
  • Powders are prepared quite simply by comminuting the active ingredient to a suitably fine size and mixing with a similarly comminuted diluent.
  • the diluent can be an edible carbohydrate material such as lactose or starch.
  • a sweetening agent or sugar is present as well as flavoring oil.
  • Capsules are produced b preparing a powder mixture as hereinbefore described and filling into formed gelatin sheaths.
  • a lubricant such as talc, magnesium stearate, calcium stearate and the like is added to the powder mixture before the filling operation.
  • Soft gelatin capsules are prepared by machine encapsulation of slurry of active ingredients with an acceptable vegetable oil, light liquid petrolatum or other inert oil or triglyceride.
  • Tablets are made by preparing a powder mixture, granulating or slugging, adding a lubricant and pressing into tablets.
  • the powder mixture is prepared by mixing an active ingredient, suitably comminuted, with a diluent or base such as starch, lactose, kaolin. dicaicium phosphate and the like.
  • the powder mixture can be granulated by wetting with a binder such as corn symp, gelatin solution, niethylcellulose solution or acacia mucilage and forcing through a screen
  • the powder mixture can be slugged, i.e., ran through the tablet machine and the resulting imperfectly formed tablets broken into pieces (slugs).
  • the slugs can be lubricated to prevent sticking to the tablet- forming dies by means of the addition of stearic acid, a stearic salt talc or mineral oil The lubricated mixture is then, compressed into tablets.
  • the tablet can be provided with a protective coating consisting of a sealing coat or enteric coat of shellac, coating of sugar and methyl cellulose and polish coating of carnauba wax.
  • Fluid unit dosage forms for oral administration such as in syrups, elixirs and suspensions can be prepared wherein each teaspoonful of composition contains a predetermined amount, of an active ingredient for administration.
  • the water-soluble forms can be dissolved in an aqueous vehicle together with sugar, flavoring agents and preservatives to form a syrup.
  • An elixir is prepared by using a hydroalcoholie vehicle with suitable sweeteners together with a flavoring agent.
  • Suspensions can be prepared of the insoluble forms with suitable vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.
  • fluid unit dosage forms are prepared utilizing an active ingredient and a sterile vehicle, water being preferred.
  • the active ingredient depending on the form and concentration used, can be either suspended or dissolved in the vehicle, in preparing solutions the water- soluble active ingredient can be dissolved in water for injection and filter sterilized before filling into suitable vial or ampule and sealing.
  • adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle
  • Parenteral suspensions are prepared in substantially the same manner except that an active, ingredient is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
  • the active ingredient can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredient.
  • An active ingredient can be administered by means of a suppository.
  • a vehicle which has a melting point at about body temperature or one that is readily soluble can be utilized.
  • coco butter and various polyethylene glycols (Carbowaxes) can serve as the vehicle.
  • a fluid unit dosage form is prepared utilizing an active ingredient and a suitable pharmaceutical vehicle, preferably P.F. water, a dry? powder can be formulated ' when insufflation is the admini stration of choice.
  • the active ingredients can be packaged in a pressurized aerosol container together with a gaseous or liquified propellant, for example, dichlorodifluoromethane, carbon dioxide, .nitrogen, propane, and the like, with the usual adjuvants such as cosol vents and wetting agents, as may be necessary or desirable.
  • a gaseous or liquified propellant for example, dichlorodifluoromethane, carbon dioxide, .nitrogen, propane, and the like, with the usual adjuvants such as cosol vents and wetting agents, as may be necessary or desirable.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal subjects., each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle.
  • the specifications for the novel unit dosage forms of this invention are dictated by and are directly dependent on (a) the unique characteristics of the active material and the parti cuiar therapeutic effect to be achieved, and (b) the limitation inherent in the ait of compounding such an active material for therapeutic use in humans, as disclosed in this specification, these being features of the present invention.
  • suitable unit dosage forms in accord with this invention are tablets, capsules, troches, suppositories, powder packets, wafers, cachets, teaspoon&is, tablespoonfuls, dropperfuis, ampules, vials, segregated multiples of any of the foregoing, and other forms as herein described.
  • the tablets of the present invention contain one or more pharmaceutically active agents that are released therefrom upon contact of the tablet with a liquid medium, for example a dissolution medium such as gastrointestinal fluids.
  • a liquid medium for example a dissolution medium such as gastrointestinal fluids.
  • Water soluble as used herein in connection with non-polymeric materials, shall mean from sparingly soluble to very soluble, i.e., not more than 100 parts water required to dissolve 1 part of the non- polymeric, water soluble solute. See Remington, The Science and Practice of Pharmacy, pp 208-209 (2000).
  • Water soluble as used herein in connection with polymeric materials, shall mean that the polymer swells in water and can be dispersed at the molecular level or dissolved in water.
  • modified release shall apply to tablets, matrices, particles, coatings, portions thereof, or compositions that alter the release of an pharmaceutically active agent in any manner.
  • Types of modified release include controlled, prolonged, sustained, extended, delayed, pulsatile, repeat action, and the like. Suitable mechanisms for achieving these types of modified, release include diffusion, erosion, surface area control via geometry and/or impermeable barriers, or other mechanisms known in the art.
  • the first pharmaceutically active agent and the hydrophiiic polymer are mixed with a powder containing a pharmaceutically- acceptable carrier, which is also defined herein as the tabiet matrix.
  • the powder has an average particle size of about 50 microns to about 500 microns, such as between 50 microns and 300 microns. Particles in this siz range are particularly useful for direct compression processes.
  • the components of powder are blended together, for example as dry powders, and fed into the die cavity of an apparatus that applies pressure to form a tablet core.
  • Any suitable compacting apparatus may be used, including, but not limited to, conventional unitary or rotary tabiet press.
  • the tablet core may be formed by compaction using a rotary tabiet press (e.g., such as those commercially available from Fette America inc., Rockaway, N.J., or Manesty Machines LTD, Liverpool, UK).
  • a metered volume of powder is filled into a die cavity (where the powder is either gravity fed or mechanically fed from a feeder) of the rotary tablet press, and the cavity rotates as part of a "die table" from the filling position to a compaction position.
  • the powder is compacted between an upper and a lower punch, then the resulting tablet core is pushed from the die cavity by the lower punch and then guided to an injection chute by a stationary "take-off bar.
  • the tablet core may be a directly compressed tablet core made from a powder that is substantially free of water-soluble polymeric binders and hydrated polymers.
  • substantially free is less than 5 percent, such as less than i percent, such as less than 0.1 percent, such as completely free (e.g., 0 percent).
  • This composition is advantageous for minimizing processing and material costs and providing for optimal physical and chemical stability of the tablet core.
  • the density of the tablet core is greater than about 0 9 g/ce,
  • the table core may have one of a variety of different shapes.
  • the tablet core may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like; or may have the geometry of a space figure with some non-flat faces, such as a cone, truncated cone, cylinder, sphere, torus, or the like.
  • a tablet core has one or more major faces.
  • the tablet core surface typically has opposing upper and lower faces formed by contact with the upper and lower punch faces in the compression machine, in such embodiments the tablet core surface typically further includes a "belly-band" located between the upper and lower faces, and formed by contact with the die wails in the compression machine.
  • the tablet core contains one or more hydrophilic polymers.
  • Suitable hydrophilic polymers include, but are not limited to, water swellable cellulose derivatives, polyalkyiene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloitls, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof.
  • suitable water swellable cellulose derivatives include, but are not limited to, sodium carboxymethylcellulose, cross-linked hydroxypropylcelluSose, hydro ypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutyiceiiulose, hydroxyphenylcellulose, hydroxyethy 1 cell utose (HEC), hydroxypentylcellulose, hydroxypropylethy lcell ulose, h droxypropylbutylcel lulose, and hydroxypropylethylcellu!ose, and mixtures thereof.
  • suitable polyalkylene glycols include, but are not limited to, polyethylene glycol.
  • thermoplastic polyalkylene oxides include, but are not limited to, poly (ethylene oxide).
  • suitable acrylic polymers include, but are not limited to, potassium memacrylatedivinylbenzene copolymer, polymethylmethacrylate, high-molecular weight crosslinked acrylic acid homopoly ers and copolymers such as those commercially available from. Noveoo Chemicals under the tradename CARBOPOL rM .
  • hydrocolloids include, but are not limited to, alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, geiian gum, maltodextrin, gaiaciomannan, pusstulan, laminarin, sclerogiucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methyl an, ehitm, cyciodextriii, chitosan, and mixtures thereof.
  • Suitable clays include, but are not limited to, smectites such as bentonite, kaolin, and laponite; magnesium trisilicate; magnesium aluminum silicate; and mixtures thereof.
  • suitable gelling starches include, but are not, limited to, acid hydrolyzed starches, swelling starches such as sodium starch glycolate and derivati es thereof and mixtures thereof.
  • suitable swelling cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolido.ne, cross-linked agar, and cross-linked carboxymethylcelluiose sodium, and mixtures thereo
  • an osmogen is incorporated into the tablet core in order to draw water into the tablet upon contact with fluids, such as gastrointestinal fluids.
  • An osmogen as used herein is a water soluble component which preferentially draws water into the tablet core for the purposes of distributing the water throughout the core, so that the active ingredient contained in the core may be released.
  • the osmogen is a salt such as but not limited to sodium chloride, potassium chloride, sodium citrate, or potassium citrate,
  • the carrier may contain one or more suitable excipients for the formulation of tablets.
  • suitable excipients include, but are not limited to, fillers, adsorbents, binders, disintegrants, lubricants, giidants, release-modifying excipients, superdisintegrants, antioxidants, and mixtures thereof,
  • Suitable fillers include, but are not limited to. watersoluble compressible carbohydrates such as sugars (e.g., dextrose, sucrose, maltose, and lactose), starches (e.g., corn starch), sugar-alcohols (e.g.. mannitoi, sorbitol , maltitol, ci vihritol, and xy!itol), starch hydrolysates (e.g., dextrins, and .maltodextrins), and water insoluble plasticall deforming materials (e.g., microcrystalline cellulose or other cellulosic derivatives ⁇ , and mixtures thereof.
  • watersoluble compressible carbohydrates such as sugars (e.g., dextrose, sucrose, maltose, and lactose), starches (e.g., corn starch), sugar-alcohols (e.g.. mannitoi, sorbitol , maltitol, ci
  • Suitable adsorbents include, but are not limited to, water-insoluble adsorbents such as dicalcium phosphate, tri calcium phosphate, silicified microcrystalline cellulose (e.g., such as distributed under the PROSOLV brand (PenWesi Pharmaceuticals, Patterson, N Y.)), magnesium aluminum etasilicate (e.g., such as distributed under the NEUS1LINTM brand (Fuji Chemical industries (USA) Inc., Robfainsville, .J.), clays, silicas, bentonite, zeolites, magnesium silicates, hydrotalcite, veegum, and mixtures thereof.
  • water-insoluble adsorbents such as dicalcium phosphate, tri calcium phosphate, silicified microcrystalline cellulose (e.g., such as distributed under the PROSOLV brand (PenWesi Pharmaceuticals, Patterson, N Y.)), magnesium aluminum etasilicate (e.g., such as distributed under the
  • Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrolidone and hydroxypropylmethylcellulose; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, earboxymethyicellulose, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, mulin, wheian, rhamsan, zooglan, methylan, chitin, eyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, and starches; and mixtures thereof.
  • dry binders such as polyvinyl pyrrolidone and hydroxypropyl
  • Suitable disintegrates include, but are not limited to, sodium starch gl col ate, cross-linked polyvinylpyrrolidone, cross-] inked carboxyniethy lcel lulose, starches, microcrystalline cellulose, and mixtures thereof.
  • Suitable lubricants include, but are not limited to, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures thereof.
  • Suitable gl id ants include, but are not limited to, colloidal silicon dioxide.
  • Suitable release-modifying exctpients include, but are not limited to, insoluble edible materials, pH-dependent polymers, and mixtures thereof
  • Suitable insoluble edible materials for use as release-modifying excipients include, but are not limited to, water-insoluble polymers and low-melting hydrophobic materials, copolymers thereof, and mixtures thereof
  • suitable water- insoluble polymers include, but are not limited to, ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acry!ates, methacrylates. acrylic acid copolymers, copolymers thereof, and mixtures thereof.
  • Suitable low-melting hydrophobic materials include, but are not limited to. fats, fatty acid esters, phospholipids, waxes, and mixtures thereof.
  • suitable fats include, but are not limited to, hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated. sunflower oil, and hydrogenated soybean oil, free fatty acids and their salts, and mixtures thereof.
  • suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, di-, and triglycerides, glyceryl behenate, glyceryl palmitostearate.
  • phospholi ids include phosphatidyl choline, phosphatidyl serene., phosphoiidyl enositol, pliosphotidie acid, and mixtures thereof.
  • suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, macrocrystalline wax, and paraffin wax; fat-containing .mixtures such as chocolate, and mixtures thereof.
  • suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, macrocrystalline wax, and paraffin wax; fat-containing .mixtures such as chocolate, and mixtures thereof.
  • super disintegrants include, but are not limited to. croscarmel!ose sodium, sodium starch alveolate and cross- linked povidone (crospovidone).
  • the tablei core contains up to about 5 percent by weight of such super disititegrant.
  • Suitable spray coating techniques include spray coating via a coatin pan or fluid bed process such as Wurster coating or top spray fluid bed coating as described in the test, "The Theory and Practice of Industrial Pharmacy", Lachman, Leon et, at, 3rd ed.
  • the osmotic coating may be applied using a solution prepared with water, organic solvents, or mixtures thereof.
  • Suitable organic solvents include but are not limited to acetone, isopropanol, methylene chloride, hexane, methanol, ethanol, and mixtures thereof
  • the polymer ⁇ s) are dissolved in the coating solution.
  • the polyrner(s) are dispersed, as is the case when applying water insoluble polymers via a dispersion or as is the case when using ethyJceJ!ulose dispersions.
  • the osmotic coating functions as a semipermeable membrane (e.g., allowing water or solvent to pass into the core, but being impermeable to dissolved pharmaceutically active agent, thereby preventing the passage of pharmaceutically active agent therethrough)
  • the film former is selected from water insoluble polymers, pH-dependent polymers, water soluble polymers, and combinations thereof.
  • the osmotic coating includes a water insoluble polymer and a pore forming material.
  • water-insoluble polymers examples include ethyl cellul se, polyvinyl alcohols, polyvinyl acetate, polyeaprolactones, cellulose acetate and its derivatives, acrylates, trsethaerylates, acrylic add copolymers, and combinations thereof.
  • the water insoluble polymer is cellulose acetate.
  • the osmotic coating includes from about 10 to about 100 weight percent of a water insoluble film former.
  • the water insoluble polymer is combined with a. water soluble film former in order to create pores in the resulting semipermeable membrane.
  • suitable film formers include, but are not limited to: water soluble vinyl polymers such as polyvinylalcohol (PVA); water soluble polycarbohydrat.es such as hydroxypropyl starch, ydroxyethyl starch, pullulan, methyl ethyl starch, earhoxymethyl starch, pre-gelatinized starches, and film-forming modified starches; water swellable cellulose derivatives such as hydroxypropyl cellulose (HPC), hydroxy propylmethyl cellulose (HPMC), methyl cellulose (MC), hy droxy ethylraethy!celiul ose (HE C), h droxy butyl methyl eel iulose (BBMC), hydroxyethyl ethyl
  • HPC hydroxypropyl cellulose
  • a pH dependent polymer is incorporated into the osmotic coating.
  • the pH dependent polymer is used at a level of from about 10 to about 50 percent by weight of the osmotic coating.
  • Suitable film-forming pH- dependent polymers include, but are not limited to, enteric cellulose derivatives, such as for example hydroxy propyl methyl cellulose phthalate., hydroxypropyl meihylcelSulose acetate succinate, and cellulose acetate phthalate, natural resins such as shellac and zeiii; enteric acetate derivatives such as polyvinyl acetate phthalate, cellulose acetate phthalate, and acetaldehyde dimethyl cellulose acetate; and enteric aery late derivatives such as for example polymeihacrylate-based polymers such as poSy(methacryiic acid, methyl methacrylate) 1 :2 (commercially available from Rohm Pharma GmbH under the tradename
  • the osmotic coating has an average thickness of at least 5 microns, such as from about 10 microns to about 200 microns, e.g. from about 20 microns to about 150 microns, e.g. from about 30 to about 1 50 microns.
  • the osmotic coating is free of porosity (e.g., wherein the pore volume is in a pore diameter range of less than 0.01 g/cc).
  • the average pore diameter of the osmotic coating is less than about 0/2 microns (e.g., less than about 0.15 microns).
  • the osmotic coating is substantially free of pharmaceutically active agent, in one embodi ment the osmotic coating includes anpharmaceutically active agent which is different than the pharmaceutically active agent included in the immediate release coating.
  • the osmotic coating includes a plasticizer In one embodiment the plasticizer must be of sufficient quantity to withstand the compression force of the immediate release coating.
  • Suitable plasticizers include, but are not limited to; polyethylene glycol; propylene glycol, glycerin; sorbitol; tri ethyl citrate; iributyl citrate; dibutyl sebecate; vegetable oils such as castor oil, grape oil, olive oil, and sesame oil; surfactants such as pol sorbates, sodium laur l sulfates, and dioctyl -sodium sulfosuccinates; mono acetate of glycerol; diacetate of glycerol; triacetate of glycerol; natural gums; toacetin; acetyl tributyl citrate; diethyloxalate; diethylmalate; diethyl fumarate; diethylmalonate; dioctylphthalate; dibutylsuccinate; glycerol tributytate; liydrogenated castor oil; fatty acids such
  • At least about 50 percent of the cross-sectional area of the osmotic coating used in tablets of this invention is striated, such as at least about 80% of the cross-sectional area of the osmotic coating portion is striated.
  • striated means non-homogeneous with respect to appearance and with respect to the internal structure of the coating portion when viewed under any magnification and lighting conditions, at which point striations or layers can be viewed.
  • Compressed portions of a pharmaceutical oral dosage forms do not display striated areas, wherein spray coated portions display striations.
  • a crosssection of the osmotic coating portion is striated, and nonuniform with respect to refractive properties when observed utilizing a light microscope or a scanning electron microscope at a magnification of about 50 to about 400 times.
  • the characteristic striations are indicati ve of the spra -coating process consisting of multiple repetitions of the steps consisting of: (a) application via spraying of coating solution; followed by Cb) warm air drying, to a tumbling bed of tablets in a revolving coating pan such that numerous layers of coating material are built up as each application of coating material dries to form a layer, in one embodiment, the thickness of an indi vidual striated layer is the range of about 10 microns to about. 15 microns.
  • the osmotic coating is semipermeable (e.g., containing a plurality of small opening) and does not require the addition of an additional opening via laser or other means, in one such embodiment, the semi-permeable membrane of the osmotic coating also allows for the release of the active ingredient in the tablet core through the membrane in a zero-order or first-order release manner.
  • the immediate release coating has an average thickness of at least 50 microns, such as from about 50 microns to about 2500 microns; e.g., from about 250 microns to about 1000 microns.
  • the immediate release coating is typically compressed at a density of more than about 0.9 g/cc, as measured by the weight and volume of that specific layer,
  • the first portion contains the first pharmaceutically active agent and the second portion contains the second pharmaceutically active agent.
  • one of the portions coniatns a third pharmaceutically active agent.
  • one of the portions contains a second immedi ate rel ease portion of the same pharmaceutically active agent as that contained in the tablet core.
  • the outer coating portion is prepared as a dry blend of materials prior to addition to the coated tablet core, hi another embodiment the outer coating portion is included of a dried granulation including the pharmaceutically active agent.
  • a suitable flavor or aroma agent may be added to the outer coatiiig.
  • suitable flavor and aroma agents include, but are not limited to, essential oils including distillations, solvent extractions, or cold expressions of chopped flowers, leaves, peel or pulped whole fruit containing mixtures of alcohols, esters, aldehydes and lactones; essences including either diluted solutions of essential oils, or mixtures of synthetic chemicals blended to match, the natural, flavor of the fruit (e.g., strawberry, raspberry, and black currant); artificial and natural flavors of brews and liquors (e.g., cognac, whisky, rum, gin, sherry, port, and wine); tobacco, coffee, tea, cocoa, and mini; fruit juices including expelled juice from washed, scrubbed fruits such as lemon, orange, and lime; mint; ginger; cinnamon; cacoe/ cocoa; vanilla, liquorice; menthol; eucalyptus; aniseeds nuts (e.g., peanuts, coconuts,
  • £00124 ⁇ Formulations with different drug release mechanisms described above could be combined in a final dosage form containing single or multiple units.
  • multiple units include multilayer tablets, capsules containing tablets, beads, or granules in a solid or liquid form.
  • Typical, immediate release formulations include compressed tablets, gels, films, coatings, liquids and particles thai can be encapsulated, for example, in a gelatin capsule.
  • Many methods for preparing coatings, covering or incorporating dru3 ⁇ 4s, are known in the art.
  • the .immediate release dosage, unit of the dosage form i.e., a tablet, a plurality of drug-containing beads, granules or particles, or an outer layer of a coated core dosage form, contains a therapeutically effective quantity of the active agent with conventional pharmaceutical excipients.
  • the immediate release dosage unit may or may not he coated, and may or may not be admixed with the delayed release dosage unit or units (as in an encapsulated mixture of immediate release drug-containing granules, particles or beads and delayed release drug-containing granules or beads).
  • a preferred method for preparing immediate release tablets is by compressing a drug containing blend, e.g., blend of granules, prepared using a direct, blend, wet-granulation or dry-granulation process.
  • Immediate release tablets may also be molded rather than compressed, starting with a moist material containing a suitable water-soluble lubricant.
  • preferred tablets described herein are manufactured using compression rather than molding.
  • a preferred method for forming immediate release drug-containing blend is to mix drug particles directly with one or more excipients such as diluents (or fillers), binders, disintegrants, lubricants, glidants, and/or colorants.
  • a drug-containing blend may be prepared by using a wet-granulation or dry- granulation process.
  • Beads containing the active agent may also be prepared by any one of a number of conventional techniques, typically starting from a fluid dispersion.
  • a typical method for preparing drug-containing beads involves blending the active agent with conventional pharmaceutical excipients such as microcrystaiiine cellulose, starch, polyvinylpyrrolidone, mefhylceliulose, tale, metallic stearates, and silicone dioxide.
  • the admixture is used to coat a bead core such as a sugar sphere (e.g., "non-parcil") having a size of approximately 20 to 60 mesh.
  • An alternative procedure forpreparing drug beads is by blending tile drug with one or more pharmaceutically acceptable excipients, such as microcrystalline cellulose, lactose, cellulose, polyvinyl pyrrolidone, talc, magnesium stearate, and a disintegrant, extruding the blend, spheronizing the extrudate, drying and optionall coating the bead to form immediate release beads.
  • excipients such as microcrystalline cellulose, lactose, cellulose, polyvinyl pyrrolidone, talc, magnesium stearate, and a disintegrant
  • Extended release formulations are generally prepared as diffusion or osmotic- systems, for example, as described in "Remingto— The Science and Practice of Pharmacy", 20th Ed., Lippincott Williams & Wilkins, Baltimore, Md , 2000).
  • a diffusion system typically consists of one of two types of devices, reservoir and matrix, which are well known and described in die art.
  • the matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form.
  • the three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds.
  • Plastic matrices include, but are not limited to, methyl aery late-methyl methacryiate, polyvinyl chloride, and polyethylene.
  • Hydrophilic polymers include, but are not limited to, methylcellulose, hydroxypropy!celiulose, hydorxypropylroethylcellulose, sodium carboxymethylceUulose, and Carbopo! lM 934, and polyethylene oxides.
  • Fatty compounds include, but are not limited to, various waxes such as eamauba wax and glyceryl tristearate.
  • extended release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form. In the latter case, the desired drag release profile can be achieved by combining, low permeability and high permeability coating materials in suitable proportion.
  • An immediate release porti n can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core; using coating or compression processes or in a multiple unit system such as a capsule containing extended and immediate release beads.
  • Extended release tablets containing hydrophiiic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation processes. These formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient.
  • the usual diluents include inert powdered substances such as different kinds of starch, powdered, cellulose, especially crystalline and microcrystaliitie cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • Typical diluents include, for example, various types of starch, lactose, mannitol , kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful.
  • Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, and glucose.
  • J00130J Extended release tablets containing wax materials are generally prepared using methods known in the art such as a direct blend method, a congealing method, and an aqueous dispersion method.
  • the congealing method the drug is mixed with a wax material and either spray- congealed or congealed and screened and processed.
  • Delayed release dosage formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, hot soluble in the neutral environment of small intestines.
  • the delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with, a selected coating material.
  • the drug-containing composition may be a. tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule.
  • Preferred coating materials include bioerodible, gradually hydrolyzable.
  • Suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydoxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxy propyl methyl cellulose acetate succinate, hydroxypropylmethyJ cellulose phthalate, methylceliulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trirneliitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacr Jic acid, methyl acrylate, ethyl acry!ate, methyl methacrylate and/or ethyl metbacrylate, and other rnethacrylic resins that are commercially available under the tradename EUDRAGIT ' EM (Rohm Pharma; [0086] Westerstadt, Germany), including EUDRAGITTM
  • EUDRAGITTM 1 100D (soluble at pH 6.0 and above), EUDRAGIXFM S (soluble at pH 7.0 and above, as a result of a higher degree of esterifi cati n), and EUDRAGITTM E, RL and RS (water-insoluble polymers having different degrees of permeability and expandability); vinyl polymers and copoJymets such as polyvinyl pyrrolidone, vinyl acetate, vinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene- vinyl acetate copolymer; enzymatically degradable polymers such as azo polymers, pectin, chitosan, amylase and guar gum; zein and shellac.
  • vinyl polymers and copoJymets such as polyvinyl pyrrolidone, vinyl acetate, vinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene- vinyl acetate copolymer
  • Multi-layer coatings using different polymers may also be applied.
  • the preferred coating weights for particular coating materials may be readily determined by those skilled in the art by evaluating individual release profiles for tablets, beads and granules prepared with different quantities of various coating materials. It is the combination of materials, method, and form of application that, produce the desired release characteristics, which one can determine only from the clinical studies.
  • the coating composition may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc.
  • plasticizer is normally present to reduce the fragility of the coating, and will generally represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer.
  • typical p!asticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyi citrate, triburyi citrate, tri ethyl acetyl citrate, castor oil and acetyl ated nionoglycerides.
  • a stabilizing agent is preferably used to stabilize particles in the dispersion.
  • Typical stabilizing agents are nonionic emulsifiers such as sorbiian esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, arid will generally represent approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution.
  • One effective glidant is talc.
  • Other glidants such as magnesium stearate and glycerol monostearates may also be used.
  • Pigments such as titanium dioxide may also be used.
  • Small quantities of an ami -foaming agent such as a silicone (e.g., simethicone), may also be added to the coating composition.
  • a delayed release tablet may be formulated by dispersing tire dru within a matrix of a suitable material such as a hydrophilic polymer or a fatty compound.
  • suitable hydrophilic polymers include, but are not limited io, polymers or copolymers of cellulose, cellulose ester, acrylic acid, metiiacryltc acid, methyl aerylate, ethyl aery I ate, and vinyl or enzymatical!y degradable polymers or copolymers as described above. These hydrophilic polymers are particularly useful for providing a delayed release matrix.
  • Fatty compounds for use as a matrix material include, but are hot limited to, waxes (e,g. camauba wax) and glycerol tristearate. Once the active ingredient is mixed with the matrix material, the mixture can be compressed into tablets.
  • a pulsed release dosage form is one that mimics a multiple dosing profile without repeated dosing and typically allows at least a twofold reduction in dosing frequency as compared to the drug presented as a conventional dosage form (e.g., as a solution or promp drug-releasing, conventional solid dosage form).
  • a pulsed release profile is characterized by a time period of no release (lag time) or reduced release followed by rapid drug release.
  • Each dosage form contains a therapeutically effective amount of active agent.
  • approximatel 30 wt. % to 70 wt %, preferably 40 wt. % to 60 wt 3 ⁇ 4, of the total amount of active agent in the dosage form is released in the initial pulse, and, correspondingly approximately 70 wt. % to 3.0 wt. 3 ⁇ 4, preferably 60 wt. % to 40 wt. %, of the total amount of active agent in the dosage form is released in the second pulse.
  • the second pulse is preferably released approximately 3 hours to less than 14 hours, and more preferably approximately 5 hours to 12 hours, following administration.
  • the dosage form can be a closed capsule housing at least two drug-containing dosage units, each dosage unit containing one or more compressed tablets, or may contain, a plurality of heads, granules or particles, providing that each dosage unit has a different drug release profile.
  • the immediate release dosage unit releases drag substantially immediately following oral administration to provide an initial dose.
  • the delayed release dosage unit releases drug approximately 3 hours to 14 hours following oral administration to provide a second dose.
  • an. opiional second delayed release dosage unit releases drug about 2 hours to 8 hours following the release of the second dose, which is typically 5 hours to 18 hours foil owing oral administration.
  • Another dosage form contains a compressed tablet or a capsule having a drug- containing immediate release dosage unit, a delayed release dosage unit and an optional second delayed release dosage unit.
  • the immediate release dosage unit contains a plurality of beads, granules particles that release drug substantially immediately following oral administration to provide an initial dose.
  • the delayed release dosage unit contains a plurality of coated beads or granules, which release drug approximately 3 hours to i4 hours following oral admin stration to provide a second dose.
  • An optional second delayed release dosage unit contains coated beads or granules that release drug about 2 to 8 hours following administration of the initial delayed release dose, which is typically 5 to 18 hours following oral administration.
  • the beads or granules in the delayed release dosage unites) are coated with a bioerodibSe polymeric material. This coating prevents the drug from being released until the appropriate time, i.e. , approximately 3 hours to less than 14 hours following oral administration for the delayed release dosage unit and at least 5 hours to approximately 18 hours following oral administration for the optional second delayed release dosage unit.
  • the components may be admixed in the tablet or may be layered to form a laminated tablet,
  • Another dosage form i a tablet having a drug-containing immediate release dosage unit, a delayed release dosage unit, and an optional second delayed release dosage unit, wherein the immediate release dosage unit comprises an outer layer thai releases the drug substantially immediately following oral administration.
  • the arrangement of the remaining delayed release dosage(s) depends upon whether the dosage form is designed to mimic twice daily dosing or three times daily dosing.
  • the delayed release dosage unit contains an inner core that is coated with a bioerodible polymeric material .
  • the coating is applied such that release of the drug occurs approximately 3 hours to less than 14 hours following oral administration, in this form, the outer layer completely surrounds the inner core.
  • the (first) delayed release dose contains an interaal layer that releases drug approximatel 3 hours to less than 14 hours following oral administration . This interaal layer is surrounded by the outer layer.
  • the second delayed release dosage unit generally contains an inner core that releases the drug at least 5 hours to approximately .18 hours following oral administration.
  • the layers of this tablet (starting from the external surface) contain an outer layer, an internal layer and an inner core.
  • the inner core contains delayed release beads or granules.
  • die internal layer contains the drug coated with a bioerodible polymeric material.
  • both the delayed release dosage unit and second delayed release dosage units are surrounded fay an inner layer.
  • This inner layer is free of active agent.
  • the layers of this tablet (starting from the external surface) comprise an outer layer, inner layer and an admixture of the delayed release dosage units.
  • the first delayed release pulse occurs once the inner layer is substantially eroded thereb releasing the admixture of the delayed release dosage units.
  • the dose corresponding to the (first) delayed release dosage unit is released immediately since the inner layer has prevented access to this dose for the appropriate time, e.g., from approximately 3 hours to 10 hours.
  • the second delayed release dose is formulated to effectively delay release for at. least 5 hours to approximately 18 hours following oral administration.
  • the delayed release dose is released approximately 3 hours to up to 14 hours, more preferably approximately 5 hours to up to 12 hours, foll wing oral administration.
  • the (first) delayed release dose is released approximately 3 to 10 hours, preferably 4 hours to 9 hours, following oral administration.
  • the third dose i.e., the second delayed release dose
  • a dosage form which contains a coated core-type delivery system wherein the outer layer contains an immediate release dosage unit containing an active agent, such that the active agent therein is immediately released following oral administration; an intermediate layer there under which surrounds a core; and a core which contains immediate release beads or granules and delayed release beads or granules, such that the second dose is provided by the immediate release beads or granules and the third dose is provided by the delayed release beads or granules.
  • J00144J For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, may be prepared.
  • aqueous or partially aqueous solutions usually in about 0.1% to 5% concentration
  • Methods of preparing various pharmaceutical compositions with a certain amount of one or more compounds of formula I or other active agents are known, or will be apparent in light of this disclosure, to those skilled in this art.
  • For examples of methods of preparing pharmaceutical compositions see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19th Edition (1995).
  • subject compositions of the present application maybe iyophilized or subjected to another appropriate drying technique such as spray drying.
  • the subject compositions may be administered once, or may be divided into a number of smaller doses to be administered at varying intervals of time, dependi ng in part on the release rate of the compositions and the desired dosage
  • Formulations useful in the methods provided herein include those suitable for oral , nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well, known in the art of pharmacy.
  • the amount of a subject composition which may be combined with a carrier material to produce a single dose may vary depending upon the subject being treated, and the particular mode of administration.
  • Methods of preparing these formulations or compositions include the step of bringing into association subject compositions with the carrier and, optionally, one or more accessory-' ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a subject composition with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • the compounds of formula ⁇ described herein may be administered in inhalant or aerosol formulations.
  • the inhalant or aerosol formulations may comprise one or more agents, such as adjuvants, diagnostic agents, imaging agents, or therapeutic agents useful in inhalation therapy.
  • the final aerosol formulation may for example contain 0.005-90% w/w, for instance 0.005-50%, 0.005-5% w/w, or 0.01 -1.0% w/w, of medicament relative to the total weight, of the foramlation,
  • the formulations herein contain no components which may provoke the degradation of stratospheric ozone.
  • the formulations are substantially free of chlorofluorocarbons such as CG3F, CC12F2 and CF3CC13.
  • substantially free means less than ⁇ % w w based upon the propel 1 ant system, in particular less than 0.5%, for example 0.1% or less.
  • the propellant may optionally contain an adjuvant having a higher polarity and or a higher boiling point than the propellant.
  • Polar adjuvants which may be used include (e.g., C2-6) aliphatic alcohols and polyoSs such as ethanol, isopropanol and propylene glycol .
  • polar adjuvants e.g., 0.05-3.0% w/w
  • only small quantities of polar adjuvants e.g., 0.05-3.0% w/w
  • the formulations described herei n may contain less than 1% w/w, e.g., about 0. !% w/w, of polar adjuvant.
  • the formulations may be substantially free of polar adjuvants, such as ethanol.
  • Suitable volatile adjuvants include saturated hydrocarbons such as propane, n-butane, isobutane, pentane and isopentane and alkyi ethers such as dimethyl ether.
  • up to 50% w/w of the propellant may comprise a volatile adjuvant, for example 1 to 30% w/w of a volatile saturated C1 -C6 hydrocarbon.
  • the aerosol formulations may further comprise one or more surfactants.
  • the surfactants must be physiologically acceptable upon administration by inhalation.
  • surfactants such as L-a-phospbatidy!choHne (PC), 1,2-dipahnitoylphosphatidycholine (DFPC), oleic acid, sorbitan trioleate, sorbitan mono-oleate, sorbitan monolaurate, polyoxy ethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, natural lecithin, ole l polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, laury!
  • PC L-a-phospbatidy!choHne
  • DFPC 1,2-dipahnitoylphosphatidycholine
  • oleic acid such as L-a-phospbatidy!choHne (PC), 1,2-dipahnitoylphosphati
  • surfactants include lecithin, oleic acid, and sorbitan trioleate. 1001531 Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the disclosures herein.
  • compositions disclosed herein suitable for parenteral administration comprise one or more subject compositions in combination with one or more pharmaceutically acceptable sterile, isotonic, aqueous, or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may he reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanoL polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl o!eate.
  • ethanoL polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl o!eate.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or .nonaqueous liquid, or as an oii-m-water or waier-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin., or sucrose and acacia), each containing a predetermined amount of a subject composition as an active ingredient.
  • Subject compositions may also be administered as a bolus, electuary, or paste.
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers and/or any of the following: (i) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitof and/or silicic acid; (2) binders, such as, for example, carboxymethy I cellulose, alginates, gelatin, polyvinyl pyrrol idone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, a!ginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using a binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carhox methyl cellulose), surface-altering or dispersing agent, Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent.
  • a binder for example, gelatin or hydroxypropylmethyl cellulose
  • lubricant for example, lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carhox methyl cellulose), surface-altering or dispersing agent
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid d
  • Tablets, and other solid dosage forms may optionally be scored or prepared with coati gs and shells, such as enteric coatings and other coa tines well known in the pharmaceutical-formulating art,
  • Tablets may be plain, film or sugar coated, bisected, embossed, layered or sustained- release. They can be made in a variety of sizes, shapes and colors. Tablets may be swallowed, chewed or dissolved in the buccal cavity or beneath the tongue. They may be dissolved in water for local or topical application. Sterile tablets are normally used for parenteral solutions and for implantation beneath the skin.
  • tablets may contain a number of inert materials known as excipients. They may be classified according to the role they play in the final tablet.
  • the primary composition may include one or more of filler, binder, lubricant and glidant.
  • Other excipients which give physical characteristics to the finished tablet are coloring agents, and flavors (especially in the case of che able tablets). Without excipients most drugs and pharmaceutical ingredients cannot be directly-compressed into tablets. This is primarily due to the poor flow and cohesive properties of most drugs.
  • excipients are added to a formulation to impart good How and compression characteristics to the material being compressed. Such properties are imparted through pretreatment steps, such as wet granulation, slugging, spra drying spheronization or crystallization,
  • Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression, and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually of about 1% by weight.
  • excipients include the following: high- compressibility to allow strong tablets to be made at low compression forces; impart cohesive qualities to the powdered material; acceptable rate of disintegration; good flow properties that can improve the flow of other excipients in the formula; and cohesiveness (to prevent tablet from crumbling during processi g, shipping and handling).
  • One formulation comprises the following: a compound of Formula I, and a binder.
  • pharmaceutically acceptable binders include, but are not limited to, starches, celluloses and derivatives thereof, e.g. , rmcrocrystalline cellulose, hydroxy propyl cellulose hydroxy 1 ethyl cellulose and hydroxylpropylmethyl cellulose; sucrose; dextrose; corn syrup; polysaccharides; and gelatin.
  • the binder e.g., may be present in an amount from about 1 % to about 40% by weight of the composition such as 1 % to 30% or 1 % to 25% or 1 % to 20%.
  • one, two, three or more diluents can be added to the formulations disclosed herein.
  • examples of pharmaceutically acceptable tillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, maoottoi, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc.
  • diluents are microcrystalline cellulose which is manufactured by the controlled hydrolysis of alpha-cellulose, obtained as a pulp from fibrous plant materials, with dilute mineral acid solutions. Following hydrolysis, the hydroceUulose is purified by filtration and the aqueous slurry is spray dried to form dry, porous particles of a broad size distribution. Suitable microcrystalline cellulose will have an average particle size of from about 20 nm to about 200 am. Microcrystalline ceilulose is available from several suppliers.
  • Suitable microcrystalline cellulose includes Avicel PH 101 , Avicel PH 102, Avicel PH 103, Avicel PH 105 and Avicel PH 200, manufactured by FMC Corporation.
  • the microcrystalline cellulose ma be present in a tablet formulation in an amount of from about 25% to about 70% by weight. Another appropriate range of this material is from about 30% to about 35% by weight; yet another appropriate range of from about 30% to about 32% by weight.
  • Another diluent is lactose.
  • the lactose may be ground to have an average particle size of between about 50 tim and about 500 ⁇ prior to formulating.
  • the lactose may be present in the tablet formulati n in an amount of from about 5% to about 40% by weight, and can be from about 18% to about 35% by weight, for example, can be from about 20% to about 25% by weight.
  • A. disiniegrant is also an optional but useful component of the iablet formulation.
  • Disintegrants are included to ensure that the tablet has an acceptable rate of disintegration.
  • Typical disintegrants include starch derivatives and salts of carboxymethylceHulose.
  • Sodium starch glyeolate is one appropriate disiniegrant for thi formulation.
  • the disiniegrant is present in the tablet formulation in an amount of from about 0% to about 10% by weight, and can be from about 1% to about 4% by weight, for instance from about 1.5% to about 2.5% by weight.
  • one, two, three or more lubricants can be added to the formulations disclosed herein.
  • pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and macrocrystalline cellulose.
  • the lubricant e.g., may be present in an amount, from about. 0, 1% to about 5% by weight of the composition, whereas, the glidant, e.g., may be present in an amount from about. 0.1 % to about 10% by weight.
  • Lubricants are typically added to prevent the tahleting materials from sticking to punches, minimize friction during tablet compressio and allow for removai of the compressed tablet from the die. Such lubricants are commonl included in the final tablet mix in amounts usually less than 1% by weight.
  • the lubricant component may be hydrophobic or hydrophilic. Examples of such lubricants include stearic acid, talc and magnesium stearate. Magnesium stearate reduces the frictio between the die wall and tablet mix during the compression and ejection of the tablets. It heips prevent adhesion of tablets to the punches and dies. Magnesium stearate also aids in the flow of the powder in the hopper and into the die.
  • the lubricant has a particle size range of 450-550 microns and a density range of 1.00-1.80 g/m.L It is stable and does not polymerize within the tableting mix.
  • One lubricant, magnesium stearate may also be employed in the formulation.
  • the lubricant is present in the tablet formulation in an amount of from about 0.25% to about 6%; also appropriate is a level of about 0.5% to about 4%i by weight; and from about 0.1% to about 2% b weight.
  • Other possible lubricants include talc, polyethylene glycol, silica and hardened vegetable oils.
  • the lubricant is not present in the formulation, but is sprayed onto the dies or the punches rather than being added directly to the formul tion.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsitms, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, soiubilizing agents and emul si tiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, corn, peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, soiubilizing agents
  • Suspensions in addition to the subject compositions, may contain suspending agents such as, for example, ethoxyiaied isostearyl alcohols, polyoxyethylene sorbitol. and sorbitan esters, microcrystaliine cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
  • suspending agents such as, for example, ethoxyiaied isostearyl alcohols, polyoxyethylene sorbitol. and sorbitan esters, microcrystaliine cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppositon' wax, or a salicylate, and which is solid at room temperature, but- liquid at body temperature and, therefore, will melt in the appropriate body cavity and release the encapsulated compound(s) and compositioii(s).
  • suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppositon' wax, or a salicylate, and which is solid at room temperature, but- liquid at body temperature and, therefore, will melt in the appropriate body cavity and release the encapsulated compound(s) and compositioii(s).
  • Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations
  • he ointments, pastes, creams and gels may contain, in addition to subject compositions, other carriers, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and poiyamide powder, or mixtures of such substances.
  • Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • a transdermal patch may comprise an outer backing foil, a matri and a protective liner wherein a) the composition or compositions are present in the matrix: in a solution (which may be oversaturated), b) the matrix may contain 1 to 5% activated Si 02, and c) the matrix may have a moisture content of less than 0.7%. Moisture- free matrix patches which contain activated silicon dioxide in the matrix show an enhanced drug release into the skin.
  • a transdermal patch may comprise: a substrate sheet comprising a composite film formed of a resin composition comprising 100 parts by weigh of a poly vinyl chloride-polyurethane composite and 2-10 parts by weight of a sty rene-ethy !ene-buiyl ene-sty rene copolymer, a first adhesive layer on the one side of the composite film, and a polyalkyiene terephthalate film adhered to the one side of the composite film by means of the first adhesive layer, a primer layer which comprises a saturated polyester resin and is formed on the surface of the polyalkyiene tereplithalate film; and a second adhesive layer comprising a styrene-diene-styrene block copolymer containing a pharmaceutical agent layered on the primer layer.
  • a method for the manufacture of the above-mentioned substrate sheet comprises preparing the above resin composition molding the resin composition into a composite film by a calendar process, and then adhering a polyalkyiene terephthalate film on one side of the composite film by means of an adhesive layer thereby forming the substrate sheet, and forming a primer layer comprising a saturated polyester resin on the outer surface of the polyalkyiene terephthalate film.
  • the pharmaceutical compositions herein can be packaged to produce a "reservoir type" transdermal patch with or without a rate-limiting patch membrane.
  • the size of the patch and or the rate limiting membrane can be chosen to deliver the transdermal flux rates desired.
  • Such a transdermal patch can consist of a polypropylene/polyester impervious backing member heat-sealed to a polypropylene porous/permeable membrane with a reservoir there between.
  • the patch can include a pharmaceutically acceptable adhesive (such as a acrylate, silicone or rubber adhesive) on the membrane layer to adhere the patch to the skin of the host, e.g., a mammal such as a human.
  • A. release liner such as a polyester release liner can also be provided to cover the adhesive layer prior to application of the patch to the skin as is conventional in the art.
  • This patch assembly can be packaged in an aluminum foii or other suitable pouch, again as is conventional in the art.
  • compositions herein can be formulated into a "matrix-type" transdermal patch.
  • Drug Delivery Systems Characteristics and Biomedical Application, R. L Juliano, ed., Oxford Universit Press. N Y. (1980); and Controlled Drug Delivery, Vol. 1 Basic Concepts, Stephen D. Brack (1983) describe the theory and application of methods useful for transdermal delivery systems.
  • the drug-matrix could be formed utilizing various polymers, e.g. silicone, polyvinyl alcohol.
  • the "drug matrix” may then be packaged into an appropriate transdermal patch
  • Another type of patch comprises incorporating the drug directly in a pharmaceutically acceptable adhesive and laminating the drug-containing adhesive onto a suitable backing member, e.g. a polyester backing membrane.
  • the drug should be present at a concentration which will not affect the adhesive properties, and at the same time deliver the required clinical dose.
  • Transdermal patches may be passive or active. Passive transdermal drug delivery systems currently available, such as the nicotine, estrogen and nitroglycerine patches, deliver smali-molecuie dmgs. Many of the newly developed proteins and peptide drugs are too large to be delivered through passive transdermal patches and may be delivered using technology such as eiectrical assist (iontophoresis) for large-molecule drugs.
  • eiectrical assist iontophoresis
  • kits it may be desirable to administer in the form of a kit, it may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet.
  • the kit comprises directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
  • Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the iike). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a plastic material that may be transparent. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • Samples of body fluids can be obtained by well known techniques and include, preferably, samples of blood, plasma, serum, or urine, more preferably, samples of blood, plasma or serum.
  • Tissue or organ samples may be obtained from any tissue or organ by, e.g., biopsy.
  • Separated cells may be obtained from the body fluids or the tissues or organs by separating techniques such a centrifugation or cell soiling.
  • cell-, tissue- or organ samples are obtained from those cells, tissues or organs which express or produce the peptides referred to herein.
  • compositions and methods for treating cancer and its metastasis and their complications are provided among other things. While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the systems and methods herein will become apparent to those skilled hi the art upon review of this specification. The full scope of the claimed systems and methods should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

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Abstract

La présente invention concerne des composés de formule I ou leurs sels pharmaceutiquement acceptables, ainsi que des polymorphes, énantiomères, stéréoisomères, solvates et hydrates de ceux-ci. Ces sels peuvent être formulés en tant que compositions pharmaceutiques. Les compositions pharmaceutiques peuvent être formulées pour une administration orale non invasive, invasive, intraveineuse, une administration transdermique ou une injection. De telles compositions peuvent être utilisées pour le traitement du cancer et de sa métastase ou de ses complications associées.
PCT/IB2012/053650 2011-08-02 2012-07-17 Compositions et méthodes pour le traitement du cancer WO2013017977A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014141057A3 (fr) * 2013-03-12 2015-02-19 Mahesh Kandula Compositions et méthodes de traitement du cancer

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009049132A1 (fr) * 2007-10-12 2009-04-16 Supergen, Inc. Dérivés de quinoline servant à moduler la méthylation de l'adn

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009049132A1 (fr) * 2007-10-12 2009-04-16 Supergen, Inc. Dérivés de quinoline servant à moduler la méthylation de l'adn

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014141057A3 (fr) * 2013-03-12 2015-02-19 Mahesh Kandula Compositions et méthodes de traitement du cancer

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